Statins for Venous Event Reduction in Patients With Venous Thromboembolism

Phase 3

Recruiting

• Conditions: Blood Clot; Post Thrombotic Syndrome; Venous Thromboembolism
• Interventions: Drug: Rosuvastatin Calcium; Drug: Placebo Oral Tablet

• Registration Number: NCT04319627
• Lead Sponsor: Ottawa Hospital Research Institute

Brief Summary

The standard or usual treatment for patients diagnosed with deep vein thrombosis or pulmonary embolism is treatment with blood thinners (called anticoagulants).

While treatment of blood clots with blood thinners is effective, some research has shown that adding a statin (medication used to lower cholesterol) may give extra protection. It is thought that statins can improve how cells along the walls of the vein control inflammation, which can prevent new blood clots from forming.

The medication in this study, rosuvastatin, is approved in Canada for use as a cholesterol-lowering medication. The use of rosuvastatin in this study is considered investigational. This means that Health Canada has not approved the use of rosuvastatin as a treatment for blood clots. However, it has been approved for use in this research study.

The purpose of this study is to examine if adding a statin (rosuvastatin) to the usual blood thinner treatment will decrease the risk of another blood clot forming. The investigators also hope to discover if taking a statin reduces damage to your veins. To do this, some of the participants in this study will get rosuvastatin and others will receive a placebo (a substance that looks like the study rosuvastatin but does not have any active or medicinal ingredients). The placebo in this study is not intended to have any effect on your blood clot. A placebo is used to make the results of the study more reliable.

Detailed Description

Recent research has demonstrated that it is plausible that statins have additive, and potentially even synergistic effects, in reducing recurrent VTE in patients managed with anticoagulant-based strategies. Furthermore, it is plausible that statins may reduce the risk of recurrent VTE in those not on anticoagulants and therefore offer an alternative in patients with contraindications to anticoagulants (e.g. after major intracranial bleed), who refuse to take anticoagulants long-term (e.g. due to lifestyle modifications or fear of bleeding) or who cannot afford anticoagulants (e.g. vulnerable or impoverished populations). Finally, statins may also provide protection from recurrent VTE in patients who are not fully compliant with anticoagulant therapy. However, no known RCTs have been done to explore these possibilities.

This study aims to determine if generic rosuvastatin reduces the risk of recurrent VTE compared to placebo in patients with symptomatic major VTE.

Primary Objectives

- To determine the primary outcome event rate (i.e. symptomatic recurrent major VTE \[proximal DVT or segmental or larger PE\]) in patients taking generic rosuvastatin compared to placebo.

Secondary Objectives

* To determine the major bleeding event rate in patients taking generic rosuvastatin compared to placebo.

* To explore if rosuvastatin reduces the incidence of PTS, as measured by the Villalta scale at end of study.

Study Timeline

• Study First Submitted: 2020-03-20
• Study First Submitted QC: 2020-03-23
• Study First Posted: 2020-03-24
• Study Start: 2021-02-10
• Status Verified: 2023-05
• Last Update Submitted: 2023-05-30
• Last Update Posted: 2023-05-31
• Primary Completion: 2026-01
• Study Completion: 2027-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 2700

Inclusion Criteria

1. Symptomatic objectively confirmed proximal leg DVT (above the trifurcation of the popliteal vein) and/or PE (segmental or greater) diagnosed in the last 30 days.

Exclusion criteria

1. Unable or unwilling to provide written informed consent;

2. ≤ 18 years of age;

3. Women of childbearing potential unwilling to use appropriate contraception;

4. Currently prescribed a statin;

5. A known medical history or current diagnosis of any of the following for which statins are indicated in secondary prevention:

   1. Diabetes;
   2. Abdominal aortic aneurysm;
   3. Peripheral arterial disease;
   4. Stroke;
   5. Transient ischemic attack (TIA);
   6. Myocardial infarction (MI);
   7. Acute coronary syndromes;
   8. Stable/unstable angina;
   9. Coronary or other arterial revascularization;

6. Known diagnosis of hypercholesterolemia or dyslipidemia;

7. Contraindication to rosuvastatin;

   1. Known hypersensitivity or intolerance to statins;
   2. History of muscle disorders or statin-related muscle pain;
   3. Known liver disease (active liver disease, e.g. Hepatitis A, B, C, non-alcoholic fatty liver);
   4. Chronic kidney disease (creatinine clearance < 30ml/min);
   5. Currently pregnant or breast feeding;
   6. Taking cyclosporine;
   7. Taking atazanavir/ritonavir;
   8. Taking darolutamide;
   9. Taking regorafenib;

8. Unstable medical or psychological condition that would interfere with trial participation.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Rosuvastatin	Rosuvastatin Calcium	Participants randomized to the experimental arm will take one rosuvastatin 20 mg tablet by mouth every day for the duration of their participation in the study.
Placebo	Placebo Oral Tablet	Participants randomized to the control arm will take one placebo tablet by mouth every day for the duration of their participation in the study.

Primary Outcome Measures

Name	Time	Method
Recurrent Major VTE	Up to 60 months	Symptomatic recurrent major VTE (proximal DVT or segmental or larger PE) occurring between randomization and the end of follow-up (i.e. completion of the trial) in patients taking generic rosuvastatin as compared with placebo.

Secondary Outcome Measures

Name	Time	Method
Post Thrombotic Syndrome	Up to 60 months	Post-thrombotic syndrome as measured by the Villalta scale throughout the follow-up period in patients taking generic rosuvastatin as compared with placebo. The Villalta PTS scale has been adopted by the International Society on Thrombosis and Haemostasis (ISTH) as a standard to diagnose and grade the severity of PTS in clinical studies.; Points are summed to yield total score: 0-4: No PTS; 5-9: Mild PTS; 10-14: Moderate PTS; 15 or more, or presence of ulcer: Severe PTS.
Number of participants diagnosed with an arterial vascular event during follow-up	Up to 60 months	Components of composite arterial vascular events (see below) occurring between randomization and the end of follow-up (i.e. completion of the trial) in patients taking generic rosuvastatin as compared with placebo.; Components of composite arterial vascular events: * Fatal myocardial infarction; * Non-fatal myocardial infarction; * Hospitalization for unstable angina; * Coronary artery revascularization; * Sudden cardiac death; * Ischemic stroke.
Number of participants diagnosed with non-major VTE during follow-up	Up to 60 months	Symptomatic non-major VTE (see below) occurring between randomization and the end of follow-up (i.e. completion of the trial) in patients taking generic rosuvastatin as compared with placebo.; Non-major VTE: * Distal DVT (distal to the trifurcation of the popliteal vein); * Isolated sub-segmental PE; * Upper extremity DVT; * Superficial phlebitis \> 5 cm; * Superficial phlebitis ≤ 5 cm.
Number of deaths during study participation	Up to 60 months	All-cause mortality occurring between randomization and the end of follow-up (i.e. completion of the trial) in patients taking generic rosuvastatin as compared with placebo.

Trial Locations

Locations (18)

University Health Network; 🇨🇦 Toronto, Ontario, Canada

Jewish General Hospital; 🇨🇦 Montreal, Quebec, Canada

University of Insubria; 🇮🇹 Varese, Italy

Mater Misericordiae University Hospital; 🇮🇪 Dublin, Ireland

Amsterdam University; 🇳🇱 Amsterdam, Holland, Netherlands

Ostfold Hopsital; 🇳🇴 Sarpsborg, Norway

Foothills Medical Centre; 🇨🇦 Calgary, Alberta, Canada

Queen Elizabeth II Hospital; 🇨🇦 Halifax, Nova Scotia, Canada

Hamilton General Hospital; 🇨🇦 Hamilton, Ontario, Canada

St. Joseph's Healthcare; 🇨🇦 Hamilton, Ontario, Canada

Juravinski Hospital; 🇨🇦 Hamilton, Ontario, Canada

The Ottawa Hospital; 🇨🇦 Ottawa, Ontario, Canada

Hôpital Montfort; 🇨🇦 Ottawa, Ontario, Canada

Sunnybrook Hospital; 🇨🇦 Toronto, Ontario, Canada

Niagara Health - St. Catharines Site; 🇨🇦 St. Catharines, Ontario, Canada

CHU de Quebec-Université Laval; 🇨🇦 Quebec City, Quebec, Canada

McGill Univeristy Health Centre; 🇨🇦 Montreal, Quebec, Canada

Brest University Hospital Centre; 🇫🇷 Brest, France